DNA damaging cytotoxic chemotherapeutic agents and ionizing radiation are the mainstay of current cancer treatment regimens. These therapies are effective, especially when administered in combinations, against a wide variety of neoplasms and are likely to remain the standard of care for cancer treatment for the foreseeable future. These agents, due to their mechanism of action, have limitations which restrict their overall effectiveness. As these agents target DNA, they are effective against any cell especially those actively replicating and therefore lack tumor cell specificity. Administration is usually at the maximum tolerated dose (MTD) resulting in a narrow therapeutic index and toxicity to normal tissue especially those with an actively dividing cell component such as the gastrointestinal tract, hematological system and other organs. Acquired or intrinsic resistance can further limit the usefulness of these agents making many patients' tumors refractory to the drug. Multiple mechanisms can contribute to acquired resistance including reduced cellular levels of active drug (through increased metabolism, detoxification or active efflux), increased DNA repair, loss of p53 or attenuation of apoptotic signaling.
Despite inducing DNA damaging through multiple mechanisms (e.g. topoisomerase inhibition, direct DNA alkylation or reduction of deoxyribonucleotides), DNA damaging cytotoxic chemotherapeutic agents such as cisplatin, irinotecan or gemcitabine activate cell cycle checkpoints. Cell cycle checkpoints exist to protect the fidelity of DNA replication and division, and ensure the correct timing of cell cycle events. As DNA cannot be replaced, these pathways are critical in protecting genomic integrity and preventing the onset of cancer. Checkpoints exist at multiple phases of the cell cycle and can be activated during the G1-, S- or G2-phase of the cell cycle in response to DNA damage. Alternatively, the mitotic checkpoint is activated by improper chromosome attachment to a bipolar spindle and exists to ensure accurate chromosome segregation and protect against aneuploidy. In mammalian cells, the key effector proteins are p53 and the checkpoint kinases Chk1 and Chk2. A large proportion of human cancers are defective for the p53-pathway in some form thereby lacking a functional G1 checkpoint. Therefore, these human tumors are highly reliant on the Chk kinases to protect them in response to DNA damaging insults.
DNA damaging agents, along with ionizing radiation, activate DNA damage checkpoints and induce cell cycle arrest in G1, S, or at the G2-M transition. Damage sensors, such as the Mre11 complex (Mre11, Rad50 and Nbs1) that recognize double strand breaks, or the Rad17 and the Rad9-Hus1-Rad1 complex that recognize replication stress, activate the central transducing kinases ATM and ATR. In turn, these kinases directly activate the effector kinases Chk1 and Chk2. Chk1 and Chk2 negatively regulate the Cdc25 family of phosphatases thereby preventing cell cycle progression as well as directly modulating repair proteins resulting in increased lesion repair. This allows the cell to pause replication, repair the damaged DNA, then resume replication. Biochemical and genetic studies have demonstrated Chk1 to be essential and indispensable for the S- and G2-M checkpoints.
Chk1 inhibition, therefore, represents a novel therapeutic strategy to increase the lethality of DNA-damaging chemotherapeutic drugs in p53 pathway defective cancers. Abrogation of the remaining intact checkpoint should result in increased tumor cell death. Chk1 inhibitors have demonstrated potentatiation of a range of cytotoxic chemotherapy drugs both in vitro and in a range of pre-clinical models of human cancer including gemcitabine, irinotecan and paclitaxel. This “synthetic lethality” approach should increase the therapeutic activity of the chemotherapeutic drug without increasing the systemic toxicity as normal cells should remain protected by their functional p53 pathway. Chk1 inhibitors have, therefore, the potential to be combined with a wide range of cytotoxic chemotherapeutic agents for the treatment of a diverse selection of human cancers. This approach has started to be tested clinically with several small molecule inhibitors of Chk1 (GDC0425, GDC0575, LY2603618 and LY2606368) currently undergoing Phase I/II clinical evaluation in combination with gemcitabine, irinotecan and cytarabine. Additional agents including AZD7762, PF00477736, SCH900776 and XL844 have undergone Phase I trials but the development of these agents has subsequently been stopped.
WO2009140320 and WO2009089352 disclose pyrrolopyridines as CHK1 and/or CHK2 inhibitors.
It has now been found that certain 1H-pyrrolo[2,3-b]pyridine derivatives show efficacy as CHK1 inhibitors.